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There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.

When compared to women aged 20-29, all teen pregnancies were associated with higher rates of poor obstetric outcomes. Other factors besides teen pregnancy appear to be responsible for poor outcomes in certain ethnic groups.

Purpose: The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs.However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hCTR1) degradation and increase platinum accumulation in ovarian cancer cells. Experimental Design: The effects of bortezomib on human hCTR1 expression and cisplatin accumulation were measured by Western blot, flow cytometric, and confocal digital imaging analyses. Platinum accumulation was measured by inductively coupled plasma mass spectrometry and bortezomib concentrations by liquid chromatography/mass spectrometry. Results: Bortezomib blocked the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increased cisplatin uptake 1.6-to 2.4-fold. Median effect analysis showed a combination index of 0.37 at 50% cell kill, indicating a high level of synergy. The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation. I.p. administration of bortezomib produced a peritoneal/plasma area under the curve ratio of 252 in a murine model. I.p. administration of bortezomib before i.p. cisplatin increased platinum accumulation in peritoneal tumors by 33% (P = 0.006). Conclusions: Proteasomal inhibition prevented cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner. Bortezomib shows a large pharmacologic advantage when administered i.p. There is a strong rationale for the combined i.p. administration of bortezomib and cisplatin.